Tumors, Igf-2, And Hypoglycemia: Insights From The Clinic, The Laboratory, And The Historical Archive

Yevgeniya Dynkevich, Kristina I. Rother, Ian Whitford, Sana Qureshi, Sneha Galiveeti, Alessandra L. Szulc, Ann Danoff, Tracy L. Breen, Nargess Kaviani, Michael H. Shanik, Derek LeRoith, Riccardo Vigneri, Christian A. Koch, Jesse Roth

Research output: Contribution to journalReview articlepeer-review

116 Scopus citations


Tumors of mesenchymal and epithelial origin produce IGF-2, which activates pathways in the tumors. In a minority of patients, the tumors (hepatomas, fibromas, and fibrosarcomas are the most common among many) release into the circulation enough IGF-2-related peptides to mimic the fasting hypoglycemia characteristic of patients with insulin-producing islet-cell tumors. Rarely, markedly elevated IGF-2 levels produce somatic changes suggestive of acromegaly. Typically, the elevated IGF-2 levels are associated with suppressed plasma levels of insulin, IGF-1, and GH. Complicating the pathophysiology are the IGF binding proteins (IGFBPs) that can bind IGF-2 and IGF-1, modifying hormone metabolism and action. IGFBP concentrations are often altered in the presence of these tumors. At the cellular level, the 3 hormone-related ligands, IGF-2, IGF-1, and insulin, all bind to 4 (or more) types of IGF-1 receptor (IGF-1R) and insulin receptor (IR). Each receptor has its own characteristic affinity for each ligand, a tyrosine kinase, and overlapping profiles of action in the target cells. The IGF-2R, in addition to binding mannose-6-phosphate-containing proteins, provides an IGF-2 degradation pathway. Recent evidence suggests IGF-2R involvement also in signal transduction. Surgery, the treatment of choice, can produce a cure. For patients not cured by surgery, multiple therapies exist, for the tumor and for hypoglycemia. Potential future therapeutic approaches are sketched. From 1910 to 1930, hypoglycemia, insulin, insulinomas, and non-islet-cell tumors were recognized. The latter third of the century witnessed the emergence of the immunoassay for insulin; the IGFs, their binding proteins, and assays to measure them; and receptors for the insulin-related peptides as well as the intracellular pathways beyond the receptor. In closing, we replace non- islet-cell tumor hypoglycemia, an outdated and misleading label, with IGF-2-oma, self-explanatory and consistent with names of other hormone-secreting tumors.

Original languageEnglish
Pages (from-to)798-826
Number of pages29
JournalEndocrine Reviews
Issue number6
StatePublished - 1 Dec 2013


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